RNAseq profiling of blood from patients with coronary artery disease: Signature of a T cell imbalance.

Background: Cardiovascular disease had a global prevalence of 523 million cases and 18.6 million deaths in 2019. The current standard for diagnosing coronary artery disease (CAD) is coronary angiography either by invasive catheterization (ICA) or computed tomography (CTA). Prior studies employed single-molecule, amplification-independent RNA sequencing of whole blood to identify an RNA signature in patients with angiographically confirmed CAD. The present studies employed Illumina RNAseq and network co-expression analysis to identify systematic changes underlying CAD. Methods: Whole blood RNA was depleted of ribosomal RNA (rRNA) and analyzed by Illumina total RNA sequencing (RNAseq) to identify transcripts associated with CAD in 177 patients presenting for elective invasive coronary catheterization. The resulting transcript counts were compared between groups to identify differentially expressed genes (DEGs) and to identify patterns of changes through whole genome co-expression network analysis (WGCNA). Results: The correlation between Illumina amplified RNAseq and the prior SeqLL unamplified RNAseq was quite strong (r = 0.87), but there was only 9 % overlap in the DEGs identified. Consistent with the prior RNAseq, the majority (93 %) of DEGs were down-regulated ~1.7-fold in patients with moderate to severe CAD (>20 % stenosis). DEGs were predominantly related to T cells, consistent with known reductions in Tregs in CAD. Network analysis did not identify pre-existing modules with a strong association with CAD, but patterns of T cell dysregulation were evident. DEGs were enriched for transcripts associated with ciliary and synaptic transcripts, consistent with changes in the immune synapse of developing T cells. Conclusions: These studies confirm and extend a novel mRNA signature of a Treg-like defect in CAD. The pattern of changes is consistent with stress-related changes in the maturation of T and Treg cells, possibly due to changes in the immune synapse.

Direct Comparison of Outcomes After Transcatheter Aortic Valve Replacement in Veterans and Non-Veterans Using the Transcatheter Valve Therapy Registry.

OBJECTIVES: This study aims to compare veterans and non-veterans undergoing transcatheter aortic valve replacement (TAVR) using data from the Society for Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) registry. METHODS: Patients undergoing TAVR at George Washington University (GWU) and veterans treated at Washington DC Veterans Affairs Medical Center (VAMC) who underwent TAVR at GWU from 2014-2020 were included. All patients were reported in the TVT registry. Emergency and valve-in-valve TAVR were excluded. Cohorts were divided based on veteran status. Operators were the same for both groups. Outcomes were compared at 30 days and 1 year. The primary outcome was mortality and secondary outcomes were morbidity metrics. RESULTS: A total of 299 patients (91 veterans, 208 non-veterans) were included. Veterans had higher rates of hypertension (87.9% vs 77.9%; P=.04), diabetes (46.7% vs 28.9%; P<.01), and lung disease (2.4% vs 11.0%; P<.001). Outcomes were not significantly different between veterans and non-veterans, including 30-day mortality (0% vs 2.9%, respectively; P=.18), 1-year mortality (9.8% vs 10.7%, respectively; P=.61), stroke incidence (0% vs 2.5%, respectively; P=.73), median intensive care unit stay (24 hours in both groups), and overall hospital stay (2 days in both groups). CONCLUSIONS: The affiliation between a VAMC and an academic medical center allowed for direct comparison between veterans and non-veterans undergoing TAVR by the same operators using the TVT registry. Despite significantly higher rates of comorbidities, veterans had equivalent outcomes compared with non-veterans. This may be in part due to the comprehensive care that veterans receive in the VAMC and this institution's integrated heart center team.

RNA sequencing of blood in coronary artery disease: involvement of regulatory T cell imbalance.

BACKGROUND: Cardiovascular disease had a global prevalence of 523 million cases and 18.6 million deaths in 2019. The current standard for diagnosing coronary artery disease (CAD) is coronary angiography. Surprisingly, despite well-established clinical indications, up to 40% of the one million invasive cardiac catheterizations return a result of 'no blockage'. The present studies employed RNA sequencing of whole blood to identify an RNA signature in patients with angiographically confirmed CAD. METHODS: Whole blood RNA was depleted of ribosomal RNA (rRNA) and analyzed by single-molecule sequencing of RNA (RNAseq) to identify transcripts associated with CAD (TRACs) in a discovery group of 96 patients presenting for elective coronary catheterization. The resulting transcript counts were compared between groups to identify differentially expressed genes (DEGs). RESULTS: Surprisingly, 98% of DEGs/TRACs were down-regulated ~ 1.7-fold in patients with mild to severe CAD (> 20% stenosis). The TRACs were independent of comorbid risk factors for CAD, such as sex, hypertension, and smoking. Bioinformatic analysis identified an enrichment in transcripts such as FoxP1, ICOSLG, IKZF4/Eos, SMYD3, TRIM28, and TCF3/E2A that are likely markers of regulatory T cells (Treg), consistent with known reductions in Tregs in CAD. A validation cohort of 80 patients confirmed the overall pattern (92% down-regulation) and supported many of the Treg-related changes. TRACs were enriched for transcripts associated with stress granules, which sequester RNAs, and ciliary and synaptic transcripts, possibly consistent with changes in the immune synapse of developing T cells. CONCLUSIONS: These studies identify a novel mRNA signature of a Treg-like defect in CAD patients and provides a blueprint for a diagnostic test for CAD. The pattern of changes is consistent with stress-related changes in the maturation of T and Treg cells, possibly due to changes in the immune synapse.

The evolving role of coronary CT angiography in Acute Coronary Syndromes.

In the United States, non-obstructive coronary disease has been on the rise, and each year, nearly one million adults suffer myocardial infarction, 70% of which are non-ST-segment elevation myocardial infarction (NSTEMI). In addition, approximately 15% of patients suffering NSTEMI will have subsequent readmission for a recurrent acute coronary syndrome (ACS). While invasive angiography remains the standard of care in the diagnostic and therapeutic approach to these patients, these methods have limitations that include procedural complications, uncertain specificity in diagnosis of the culprit lesion in patients with multi-vessel coronary artery disease (CAD), and challenges in following coronary disease over time. The role of coronary computed tomography angiography (CCTA) for evaluating patients with both stable and acute chest pain has seen a paramount upshift in the last decade. This paper reviews the established role of CCTA for the rapid exclusion of obstructive plaque in troponin negative acute chest pain, while exploring opportunities to address challenges in the current approach to evaluating NSTEMI.

Resolving the topological classification of bismuth with topological defects.

The growing diversity of topological classes leads to ambiguity between classes that share similar boundary phenomenology. This is the status of bulk bismuth. Recent studies have classified it as either a strong or a higher-order topological insulator, both of which host helical modes on their boundaries. We resolve the topological classification of bismuth by spectroscopically mapping the response of its boundary modes to a screw-dislocation. We find that the one-dimensional mode, on step-edges, extends over a wide energy range and does not open a gap near the screw-dislocations. This signifies that this mode binds to the screw-dislocation, as expected for a material with nonzero weak indices. We argue that the small energy gap, at the time reversal invariant momentum L, positions bismuth within the critical region of a topological phase transition between a higher-order topological insulator and a strong topological insulator with nonzero weak indices.

Cardiovascular Disease Risk Factors and Myocardial Infarction in the Transgender Population.

BACKGROUND: As of 2016, ≈1.4 million people in the United States identify as transgender. Despite their growing number and increasing specific medical needs, there has been a lack of research on cardiovascular disease (CVD) and CVD risk factors in this population. Recent studies have reported that the transgender population had a significantly higher rate of CVD risk factors without a significant increase in overall CVD morbidity and mortality. These studies are limited by their small sample sizes and their predominant focus on younger transgender populations. With a larger sample size and inclusion of broader age range, our study aims to provide insight into the association between being transgender and cardiovascular risk factors, as well as myocardial infarction. METHODS AND RESULTS: The Behavioral Risk Factor Surveillance System data from 2014 to 2017 were used to evaluate the cross-sectional association between being transgender and the reported history of myocardial infarction and CVD risk factors. A logistic regression model was constructed to study the association between being transgender and myocardial infarction after adjusting for CVD risk factors including age, diabetes mellitus, hypertension, hypercholesterolemia, chronic kidney disease, smoking, and exercise. Multivariable analysis revealed that transgender men had a >2-fold and 4-fold increase in the rate of myocardial infarction compared with cisgender men (odds ratio, 2.53; 95% CI, 1.14-5.63; P=0.02) and cisgender women (odds ratio, 4.90; 95% CI, 2.21-10.90; P<0.01), respectively. Conversely, transgender women had >2-fold increase in the rate of myocardial infarction compared with cisgender women (odds ratio, 2.56; 95% CI, 1.78-3.68; P<0.01) but did not have a significant increase in the rate of myocardial infarction compared with cisgender men. CONCLUSIONS: The transgender population had a higher reported history of myocardial infarction in comparison to the cisgender population, except for transgender women compared with cisgender men, even after adjusting for cardiovascular risk factors.

Double Valve-in-Valve Transcatheter Valve Replacements for Failed Surgical Bioprosthetic Aortic and Tricuspid Valves.

Transcatheter technology has revolutionized the treatment of valvular disease in the field of cardiology and cardiac surgery. We present an interesting case of a patient with prior double valve replacements, which had degenerated after a decade, with symptoms of decompensated heart failure. The patient was successfully treated with double valve-in-valve transcatheter aortic and tricuspid valve replacement.

Outcomes of Acute Conduction Abnormalities Following Transcatheter Aortic Valve Implantation With a Balloon Expandable Valve and Predictors of Delayed Conduction System Abnormalities in Follow-up.

Transcatheter aortic valve implantation (TAVI) is an acceptable treatment for severe aortic stenosis in high or intermediate risk patients. Conduction abnormalities are a known complication of TAVI. Most abnormalities occur perioperatively but can develop later. The predictors of delayed conduction abnormalities are unknown. Patients who underwent TAVI at our institution were reviewed. Patients with a pre-existing pacemaker were excluded. Baseline, in-hospital, and 30-day follow-up ECGs were reviewed. Patient and procedural characteristics were analyzed to look for predictors of acute and delayed abnormalities. Ninety-eight patients were included. All valves implanted were balloon expandable, most commonly SAPIEN S3 (78%). Thirty-seven (37.7%) patients developed abnormalities before discharge. Of these patients, 20 (57.1%) had complete resolution at 30-day follow-up. No patients with new conduction abnormalities during hospitalization had additional abnormalities at 30-day follow-up. Five (5.1%) patients developed new conduction abnormalities following discharge. Overall, 22 (22.4%) patients had conduction abnormalities at 30-day follow-up which were not present at baseline. Predilatation (p = 0.003), higher ratios of balloon (p = 0.03) or valve (p = 0.05) size to left ventricular outflow tract, and previous myocardial infarction (p = 0.034) were predictive of acute conduction abnormalities. Baseline right bundle branch block (p = 0.002), longer baseline (p <0.001) and discharge (p = 0.004) QRS duration, moderate, or severe aortic insufficiency (p = 0.002) and atrial fibrillation (p = 0.031) were predictors of new conduction abnormalities after discharge. In conclusion, most new in-hospital conduction abnormalities resolve by 30-day follow-up. In-hospital conduction abnormalities are related to technical aspects of TAVI while delayed conduction abnormalities are related to baseline conduction system disease.

Pseudoaneurysm: a rare complication of distal transradial access in the anatomical snuffbox.

BACKGROUND: This report presents a case of distal radial artery pseudoaneurysm following cardiac catheterization and its successful endovascular management. Due to its novelty as a catheterization site, few to no reports exist regarding the complications associated with distal radial access. CASE PRESENTATION: A patient presented to the emergency department with severe wrist and hand swelling 48 h after successful cardiac catheterization via distal radial artery access. Angiography revealed a pseudoaneurysm which was embolized with Onyx™. Post intervention angiogram showed exclusion of the pseudoaneurysm and preservation of the left palmar arch vasculature. CONCLUSION: The case presented herein demonstrates a rare complication of distal radial access at the anatomical snuffbox.

Quasiparticle Interference Studies of Quantum Materials.

Exotic electronic states are realized in novel quantum materials. This field is revolutionized by the topological classification of materials. Such compounds necessarily host unique states on their boundaries. Scanning tunneling microscopy studies of these surface states have provided a wealth of spectroscopic characterization, with the successful cooperation of ab initio calculations. The method of quasiparticle interference imaging proves to be particularly useful for probing the dispersion relation of the surface bands. Herein, how a variety of additional fundamental electronic properties can be probed via this method is reviewed. It is demonstrated how quasiparticle interference measurements entail mesoscopic size quantization and the electronic phase coherence in semiconducting nanowires; helical spin protection and energy-momentum fluctuations in a topological insulator; and the structure of the Bloch wave function and the relative insusceptibility of topological electronic states to surface potential in a topological Weyl semimetal.

Well-differentiated bronchial neuroendocrine tumors: Clinical management and outcomes in 105 patients.

INTRODUCTION: Bronchial neuroendocrine tumors (NETs) are rare tumors representing approximately 20%-30% of all neuroendocrine tumors and 2%-3% of all adult lung cancers. Here, they present a large case series of well-differentiated bronchial NETs with the aim of investigating the behavior of these tumors and long-term outcomes. METHODS: A retrospective review was performed of 105 patients with bronchial NETs managed in a tertiary referral center in the period between January 1998 and January 2012. RESULTS: Bronchial NETs are commoner in females and the commonest presenting symptoms were cough (13.9%) and dyspnoea (11.6%). OctreoscanTM and Gallium-68 DOTATATE PET were found to have similar diagnostic sensitivity and FDG PET was more sensitive for higher-grade tumors. Over a median follow-up period of 35.5 months mortality rate was 5.7%. The 5-year survival was 76% and the 10-year survival was 62%. Female patients survived longer but this difference was not statistically significant (P = .59). Older age greater than 50 years (P = .027), higher levels of Chromogranin A (CgA) (P = .034), first-line treatment with surgery (P = .005), ki67 over 10% (P = .037), and tumor stage (P = .036) but not tumor grade (P = .22), were significantly associated with survival. DISCUSSION: Several factors have been identified which are independently associated with survival including CgA levels greater than 100 pmol/L, tumor stage, age greater than 50, ki67 over 10% and having surgery as first-line treatment. There was no difference in survival between typical and atypical carcinoids.

Robust Epitaxial Al Coating of Reclined InAs Nanowires.

It was recently shown that in situ epitaxial aluminum coating of indium arsenide nanowires is possible and yields superior properties relative to ex-situ evaporation of aluminum ( Nat. Mater. 2015 , 14 , 400 - 406 ). We demonstrate a robust and adaptive epitaxial growth protocol satisfying the need for producing an intimate contact between the aluminum superconductor and the indium arsenide nanowire. We show that the (001) indium arsenide substrate allows successful aluminum side-coating of reclined indium arsenide nanowires that emerge from (111)B microfacets. A robust, induced hard superconducting gap in the obtained indium arsenide/aluminum core/partial shell nanowires is clearly demonstrated. We compare epitaxial side-coating of round and hexagonal cross-section nanowires and find the surface roughness of the round nanowires to induce a more uniform aluminum profile. Consequently, the extended aluminum grains result in increased strain at the interface with the indium arsenide nanowire, which is found to induce dislocations penetrating into round nanowires only. A unique feature of proposed growth protocol is that it supports in situ epitaxial deposition of aluminum on all three arms of indium arsenide nanowire intersections in a single growth step. Such aluminum coated intersections play a key role in engineering topologically superconducting networks required for Majorana based quantum computation schemes.

Estimation of cardiac output and pulmonary vascular resistance by contrast echocardiography transit time measurement: a prospective pilot study.

BACKGROUND: Studies with other imaging modalities have demonstrated a relationship between contrast transit and cardiac output (CO) and pulmonary vascular resistance (PVR). We tested the hypothesis that the transit time during contrast echocardiography could accurately estimate both CO and PVR compared to right heart catheterization (RHC). METHODS: 27 patients scheduled for RHC had 2D-echocardiogram immediately prior to RHC. 3 ml of DEFINITY contrast followed by a 10 ml saline flush was injected, and a multi-cycle echo clip was acquired from the beginning of injection to opacification of the left ventricle. 2D-echo based calculations of CO and PVR along with the DEFINITY-based transit time calculations were subsequently correlated with the RHC-determined CO and PVR. RESULTS: The transit time from full opacification of the right ventricle to full opacification of the left ventricle inversely correlated with CO (r=-0.61, p<0.001). The transit time from peak opacification of the right ventricle to first appearance in the left ventricle moderately correlated with PVR (r=0.46, p<0.01). Previously described echocardiographic methods for the determination of CO (Huntsman method) and PVR (Abbas and Haddad methods) did not correlate with RHC-determined values (p = 0.20 for CO, p = 0.18 and p = 0.22 for PVR, respectively). The contrast transit time method demonstrated reliable intra- (p<0.0001) and inter-observer correlation (p<0.001). CONCLUSIONS: We describe a novel method for the quantification of CO and estimation of PVR using contrast echocardiography transit time. This technique adds to the methodologies used for noninvasive hemodynamic assessment, but requires further validation to determine overall applicability.

Three-junction SQUID-on-tip with tunable in-plane and out-of-plane magnetic field sensitivity.

Nanoscale superconducting quantum interference devices (SQUIDs) demonstrate record sensitivities to small magnetic moments but are typically sensitive only to the field component that is normal to the plane of the SQUID and out-of-plane with respect to the scanned surface. We report on a nanoscale three-junction Pb SQUID, which is fabricated on the apex of a sharp tip. Because of its three-dimensional structure, it exhibits a unique tunable sensitivity to both in-plane and out-of-plane fields. We analyze the two-dimensional interference pattern from both numerical and experimental points of view. This device is integrated into a scanning microscope, and its ability to independently measure the different components of the magnetic field with outstanding spin sensitivity better than 5 µB/Hz(1/2) is demonstrated. This highlights its potential as a local probe of nanoscale magnetic structures.

Aspirin insensitive thrombophilia: transcript profiling of blood identifies platelet abnormalities and HLA restriction.

Aspirin is the most widely used antiplatelet agent because it is safe, efficient, and inexpensive. However, a significant subset of patients does not exhibit a full inhibition of platelet aggregation, termed 'aspirin resistance' (AR). Several major studies have observed that AR patients have a 4-fold increased risk of myocardial infarction (MI), stroke, and other thrombotic events. Arachidonic acid-stimulated whole blood aggregation was tested in 132 adults at risk for ischemic events, and identified an inadequate response to aspirin therapy in 9 patients (6.8%). Expression profiling of blood RNA by microarray was used to generate new hypotheses about the etiology of AR. Among the differentially expressed genes, there were decreases in several known platelet transcripts, including clusterin (CLU), glycoproteins IIb/IIIa (ITGA2B/3), lipocalin (LCN2), lactoferrin (LTF), and the thrombopoetin receptor (MPL), but with increased mRNA for the T-cell Th1 chemokine CXCL10. There was a strong association of AR with expression of HLA-DRB4 and HLA-DQA1. Similar HLA changes have been linked to autoimmune disorders, particularly antiphospholipid syndrome (APS), in which autoantibodies to phospholipid/protein complexes can trigger platelet activation. Consistent with APS, AR patients exhibited a 30% reduction in platelet counts. Follow-up testing for autoimmune antibodies observed only borderline titers in AR patients. Overall, these results suggest that AR may be related to changes in platelet gene expression creating a hyperreactive platelet, despite antiplatelet therapy. Future studies will focus on determining the protein levels of these differential transcripts in platelets, and the possible involvement of HLA restriction as a contributing factor.

Multimodality imaging to diagnose pulmonary vein stenosis following atrial fibrillation ablation.

BACKGROUND: Atrial fibrillation (AF) is increasing in prevalence. Although experienced centers performing radiofrequency pulmonary vein isolation procedures have reported success rates approaching 72%, in rare instances it is complicated by stenosis of one or more pulmonary veins. In this report we present a case of recurrent pulmonary vein stenosis (PVS) following radiofrequency ablation for AF.

Contrast media and clotting: what is the evidence?

The rapid development of percutaneous coronary and peripheral vascular interventional technologies and also noninvasive imaging systems has led to a dramatic increase in the number of patients receiving contrast media (CM). Although relatively uncommon, adverse events can occur following administration of contrast, including nuisance reactions (e.g., nausea and urticaria) and potentially severe complications, such as contrast-induced nephropathy and thrombotic events. In this report, we review the evidence regarding the occurrence of thrombotic effects following iodinated CM administration during percutaneous coronary intervention.

Evidence based management of patients undergoing PCI. Conclusion.

A panel of leaders in the field of interventional cardiology convened to discuss the evidence-based management of patients undergoing percutaneous coronary intervention (PCI). The articles in this supplement are based on individual presentations given during the panel meeting. Following are key points of the panel's discussion and areas that the panel has indicated warrant further study.