Background: Machine learning (ML) may improve prediction of atrial fibrillation (AF), but its value compared with traditional models such as Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE-AF) in patients with diabetes remains unclear. Methods: Among 9,307 patients in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) with type 2 diabetes and no prior AF, a random forest (RF) classifier using clinical and metabolic variables was compared with a CHARGE-AF Cox model. Discrimination was assessed by five-fold cross-validated area under receiver operating curve (AUC). Results: Over 6.26 years, 175 patients developed AF. The RF model (AUC = 0.731) performed comparably to CHARGE-AF (AUC = 0.756; p = 0.18). Age, waist circumference, race, total cholesterol, and estimated glomerular filtration rate were the top predictors. Conclusion: ML matched CHARGE-AF performance and revealed distinct predictors supporting personalized AF risk prevention.

BACKGROUND:Genomewide association studies have associated >100 genetic loci with atrial fibrillation (AF), but establishing causal genes contributing to AF remains challenging.OBJECTIVE:The purpose of this study was to determine candidate novel causal genes and mechanistic pathways associated with AF risk loci by incorporating gene expression and coexpression analyses and to provide a resource for functional studies and targeting of AF-associated genes.METHODS:Cis-expression quantitative trait loci were identified for candidate genes near AF risk variants in human left atrial tissues. Coexpression partners were identified for each candidate gene. Weighted gene coexpression network analysis (WGCNA) identified modules and modules with overrepresentation of candidate AF genes. Ingenuity pathway analysis (IPA) was applied to the coexpression partners of each candidate gene. IPA and gene set over representation analysis were applied to each WGCNA module.RESULTS:One hundred sixty-six AF-risk single nucleotide polymorphisms were located in 135 loci. Eighty-one novel genes not previously annotated as putative AF risk genes were identified. IPA identified mitochondrial dysfunction, oxidative stress, epithelial adherens junction signaling, and sirtuin signaling as the most frequent significant pathways. WGCNA characterized 64 modules (candidate AF genes overrepresented in 8), represented by cell injury, death, stress, developmental, metabolic/mitochondrial, transcription/translation, and immune activation/inflammation regulatory pathways.CONCLUSION:Candidate gene coexpression analyses suggest significant roles for cellular stress and remodeling in AF, supporting a dual risk model for AF: Genetic susceptibility to AF may not manifest until later in life, when cellular stressors overwhelm adaptive responses. These analyses also provide a novel resource to guide functional studies on potential causal AF genes.

Myocardial injury after non-cardiac surgery (MINS) is common. We investigated the incidence and outcomes of MINS, and mechanistic underpinnings using pre-operative whole blood gene expression profiling in a prospective cohort study of individuals undergoing lower extremity revascularization (LER) for peripheral artery disease (PAD). Major adverse cardiovascular and limb events (MACLE) were defined as a composite of death, myocardial infarction, stroke, major lower extremity amputation or reoperation. Among 226 participants undergoing LER, MINS occurred in 53 (23.5%). Patients with MINS had a greater incidence of major adverse cardiovascular events (49.1% vs. 22.0%, adjusted HR 1.87, 95% CI 1.07–3.26) and MACLE (67.9% vs. 44.5%; adjusted HR 1.66, 95% CI 1.08–2.55) at median 20-month follow-up. Pre-operative whole blood transcriptome profiling of a nested matched MINS case–control cohort (n = 41) identified upregulation of pathways related to platelet alpha granules and coagulation in patients who subsequently developed MINS. Thrombospondin 1 ( THBS1 ) mRNA expression was 60% higher at baseline in patients who later developed MINS, and was independently associated with long-term cardiovascular events in the Duke Catheterization Genetics biorepository cohort. In conclusion, pre-operative THBS1 mRNA expression is higher in patients who subsequently develop MINS and is associated with incident cardiovascular events. Pathways related to platelet activity and coagulation associated with MINS provide novel insights into mechanisms of myocardial injury.

ABSTRACTRationaleGenome wide association studies (GWAS) have associated >100 genetic loci with atrial fibrillation (AF), yet the biological pathways of AF remain elusive.ObjectiveTo determine candidate causal genes associated with AF risk loci and their coexpression partners, modules, biologic and mechanistic pathways.Methods and ResultsCis-expression quantitative trait loci (eQTLs) were identified for candidate genes near AF risk single nucleotide polymorphisms (SNPs) in human left atrial tissues. Genes were categorized into 3 sets according to likelihood of being a causative AF gene: 1) All Candidate Genes (with significant eQTLs or previously prioritized); 2) Any eQTL Genes (with ≥1 significant eQTL); and 3) Top GWAS SNP eQTL Genes (top SNP within the top 10 eQTL SNPs). Coexpression partners were identified for each candidate gene. Weighted gene coexpression network analysis (WGCNA) identified modules and modules with overrepresentation of candidate AF genes. Ingenuity Pathway Analysis (IPA) was applied to the coexpression partners of each candidate gene, and IPA and gene set enrichment analysis (GSEA) to each WGCNA module. 166 AF-risk SNPs were located in 135 distinct loci. The All Candidate Genes group contained 233, the Any eQTL Genes group 131 (83 novel), and the Top GWAS SNP eQTL Genes group 37 genes. IPA identified mitochondrial dysfunction, oxidative stress, epithelial adherens junction signaling, and sirtuin signaling as the most frequent pathways. WGCNA characterized 64 modules; candidate AF genes were overrepresented in 8. Modules were represented by cell injury, death, stress, developmental, metabolic/mitochondrial, transcription/translation, and immune activation/inflammation regulatory pathways.ConclusionsAF candidate gene coexpression analyses suggest significant roles for cellular stress and remodeling in AF. We propose a dual risk model for AF: Genetic susceptibility to AF may not manifest until later in life, when cellular stressors overwhelm adaptive responses. These analyses provide a resource for further functional studies on potential causal AF genes.

BACKGROUND:Elevated intracardiac pressure attributable to heart failure induces electrical and structural remodeling in the left atrium (LA) that begets atrial myopathy and arrhythmias. The underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. The purpose of this study is to characterize the response of the ETV1 (ETS translocation variant 1) signaling axis in the LA during cardiac pressure overload in humans and mouse models and explore the role of ETV1 in atrial electrical and structural remodeling.METHODS:We performed gene expression profiling in 265 left atrial samples from patients who underwent cardiac surgery. Comparative gene expression profiling was performed between 2 murine models of cardiac pressure overload, transverse aortic constriction banding and angiotensin II infusion, and a genetic model of Etv1 cardiomyocyte-selective knockout (Etv1f/fMlc2aCre/+).RESULTS:Using the Cleveland Clinic biobank of human LA specimens, we found that ETV1 expression is decreased in patients with reduced ejection fraction. Consistent with its role as an important mediator of the NRG1 (Neuregulin 1) signaling pathway and activator of rapid conduction gene programming, we identified a direct correlation between ETV1 expression level and NRG1, ERBB4, SCN5A, and GJA5 levels in human LA samples. In a similar fashion to patients with heart failure, we showed that left atrial ETV1 expression is downregulated at the RNA and protein levels in murine pressure overload models. Comparative analysis of LA RNA sequencing datasets from transverse aortic constriction and angiotensin II-treated mice showed a high Pearson correlation, reflecting a highly ordered process by which the LA undergoes electrical and structural remodeling. Cardiac pressure overload produced a consistent downregulation of ErbB4, Etv1, Scn5a, and Gja5 and upregulation of profibrotic gene programming, which includes Tgfbr1/2, Igf1, and numerous collagen genes. Etv1f/fMlc2aCre/+ mice displayed atrial conduction disease and arrhythmias. Correspondingly, the LA from Etv1f/fMlc2aCre/+ mice showed downregulation of rapid conduction genes and upregulation of profibrotic gene programming, whereas analysis of a gain-of-function ETV1 RNA sequencing dataset from neonatal rat ventricular myocytes transduced with Etv1 showed reciprocal changes.CONCLUSIONS:ETV1 is downregulated in the LA during cardiac pressure overload, contributing to both electrical and structural remodeling.

Introduction: Over 135 genetic loci have been linked to atrial fibrillation (AF), yet the biological pathways of AF pathophysiology remain elusive. Weighted gene coexpression network analysis (WGCNA) constructs gene modules within a network based on correlations in gene expression, and identifies mechanisms related to AF risk. Objective: To identify biological pathways of candidate AF risk genes that will advance our understanding of AF mechanisms. Methods: RNA-sequencing was performed on left atrial appendage tissue from 265 patients. RNA-seq data were adjusted for differences in AF rhythm state and other known AF risk factors. Correlations from adjusted data were further adjusted for latent factors then spatial quantile normalized to correct for mean-variance bias. WGCNA was applied to the resulting adjusted and normalized gene-gene correlations to identify gene modules. Ingenuity Pathway Analysis and gene set over representation analysis (GSOR) were applied to each module. Results: WGCNA identified 63 modules from 17,434 genes; 47 of these contained at least one candidate AF risk gene. AF risk genes were overrepresented in 7 modules (Table 1). Notable top pathways of AF overrepresented modules include apelin signaling, heme metabolism, intracellular ion homeostasis, and the unfolded protein response. These are known to be involved in calcium signaling, iron homeostasis, glucose regulation, heat shock response, and protein ubiquitination during states of high energy demand and stress. These pathways coincide with larger cellular processes of myocyte remodeling, apoptosis, and cell survival, which were also prominent. Conclusions: Biological pathways identified through WGCNA and GSOR suggest that sustained increases in energy demand during AF promotes stress-induced cellular remodeling. Changes in calcium signaling, iron homeostasis, the unfolded protein response and glucose regulation are likely primary mechanisms of AF pathophysiology.

INTRODUCTION: The novel coronavirus SARS-CoV-2 has infected nearly 6 million people globally and resulted in over 350,000 deaths thus far. While primarily a respiratory illness, gastrointestinal (GI) manifestations have been described in up to 50.5% of patients. In a subgroup of patients, GI symptoms may be the only evidence of infection. Understanding the full spectrum of GI manifestations is crucial for recognizing affected patients and maintaining the safety of both clinicians and the public. CASE DESCRIPTION/METHODS: A 27-year-old woman with lupus presented to the emergency room with three days of abdominal pain and three weeks of cough, fevers, and malaise. Physical examination was notable for severe pain with epigastric palpation but without rebound or guarding. An abdominal CT revealed segments of small bowel wall thickening concerning for possible ischemia. An abdominal angiogram showed no evidence of mesenteric ischemia, however, exhibited small bowel inflammation. An esophagogastroduodenoscopy found atrophic, friable esophagus and circumferential ulceration of the distal duodenum. Biopsies revealed fibrin-rich thrombi within the lamina propria, and submucosa associated with mucosal necrosis. No cellular infiltration was observed to suggest vasculitis. SARS-CoV-2 nasopharyngeal PCR from admission returned positive. Rheumatology was consulted and determined that the patient's lupus was not clinically active and that microthrombi were likely related to the SARS-CoV-2 infection. The patient was discharged home on pantoprazole and apixaban with GI follow-up and instructions to self-isolate. DISCUSSION: This is the first case to date describing ulceration of the GI tract in the setting of acute SARS-CoV-2 infection. Pathology suggests the mechanism of injury to be microthrombi causing mucosal necrosis. Autopsies of recently deceased patients have similarly revealed microthrombi affecting the pulmonary and renal vasculature and it is hypothesized to be the mechanism of organ damage. Optimal medical management for hypercoagulability in the setting of SARS-CoV-2 infection remains unclear. Some authors recommend anticoagulation for 3–6 months only if venous thromboembolism (VTE) is present, while others endorse a prophylactic strategy by discharging all patients on 4–6 weeks of treatment. As SARS-CoV-2 becomes increasingly prevalent, it should be considered in the differential diagnosis of patients presenting with new onset ulcerative esophagitis or duodenitis.Figure 1.: Lower third of the esophagus. Mucosa is atrophic and friable.Figure 2.: Distal duodenum. Congested, friable mucosa with circumferential ulceration.

Background: Mesenchymal stem cells (MSC) have immunomodulatory and neuro-protective properties and are being studied for treatment of multiple sclerosis (MS). Tractography-based diffusion tensor imaging (DTI), cortical thickness (Cth) and T2 lesion volume (T2LV) can provide insight into treatment effects. Objective: The objective of this study was to analyse the effects of MSC transplantation in MS on exploratory MRI measures. Methods: MRIs were obtained from 24 MS patients from a phase 1 open-label study of autologous MSC transplantation. DTI metrics were obtained in lesions and normal-appearing white matter motor tracts (NAWM). T2LV and Cth were derived. Longitudinal evolution of MRI outcomes were modelled using linear mixed effects. Pearson's correlation was calculated between MRI and clinical measures. Results: Lesional radial diffusivity (RD) and axial diffusivity (AD) decreased pre-transplant and showed no changes post-transplant. There were mixed trends in NAWM RD and AD pre/ post-transplant. Transplantation stabilized T2LV growth. NAWM RD and AD correlated with Cth, T2LV and with leg and arm function but not with cognition. Lesional DTI demonstrated similar but less robust correlations. Conclusions: Microstructural tissue integrity is altered in MS. DTI changes pre-transplant may be influenced by concomitant lesion accrual. Contributor to DTI stabilization post-transplant is multifactorial. DTI of major motor tracts correlated well with clinical measures, highlighting its sensitivity to clinically meaningful changes.

OBJECTIVE: To determine the effect of mesenchymal stem cell (MSC) transplantation on diffusion tensor imaging (DTI) metrics from T2-lesional brain tissue in subjects with multiple sclerosis (MS) BACKGROUND: MSCs have potent immunomodulatory, tissue-protective, and repair-promoting properties in vitro and in animal models. The effect of MSCs on T2-lesional tissue in multiple sclerosis (MS) is unknown. DESIGN/METHODS: 24 subjects with relapsing forms of MS, Expanded Disability Status Scale (EDSS) 3.0-6.5, clinical or radiographic disease activity in the prior 2 years, and optic nerve involvement were enrolled into a phase I study of autologous, bone marrow derived, culture-expanded MSCs. MRI studies were performed 2 months prior to and 6 months after MSC transplantation. Lesional tissue regions-of-interest (ROI) were identified as hyperintensity on T2 FLAIR images using automated techniques. Images were subsequently co-registered with DTI data sets from which metrics were derived. Linear mixed effect modeling with likelihood ratio tests and Bonferroni correction was conducted to compare the longitudinal change in DTI metrics prior to and after MSC transplantation. Fixed effects included subject age, size of the ROI and time. Random effects included subject and individual ROI RESULTS: The evolution of DTI metrics showed no significant changes for fractional anisotropy prior to and after MSC transplantation. A progressive loss of longitudinal diffusivity (LD) (-26.6 x10-6mm2/sec/month, p <0.001) in lesional tissue was observed prior to MSC transplantation. Stabilization of LD was observed after MSC transplantation (0.9 x10-6mm2/sec/month, p=0.3). Similar effects were seen with mean and and transverse diffusivity, although the magnitude of these changes was smaller. CONCLUSIONS: MSC resulted in marked changes in DTI metrics from T2-lesional tissue of MS patients. LD has been proposed as a marker of axonal content and the stabilization of LD after MS transplantation may be evidence of decreased axonal loss. Study Supported by: KL2 TR000440/TR/NCATS NIH DoD/CDMRP W81IXWH1010270

Background: The incidence of thyroid cancers has been rising in the United States primarily due to the increased detection of well differentiated thyroid cancers (WDTC). Radioactive iodine (RAI), which is frequently used to treat WDTC, can be considered a circulating radiation emitter with the potential for mutagenic effects on hematopoietic stem cells. With a growing number of WDTC patients (pts) surviving long term following RAI therapy, establishing the risk of developing a myelodysplastic syndrome (MDS) in this cohort has important clinical implications.

Most nonenhanced MRA techniques for evaluating peripheral artery disease (PAD) require cardiac synchronization through physiological gating. Electrocardiographic gating is the most popular method for cardiac synchronization; however, it is subject to interference from switching magnetic field gradients and radiofrequency pulses. A method is described for self‐gated nonenhanced MRA that does not require the use of electrocardiographic gating. Imaging was prospectively triggered by detecting the acceleration of blood flow during systole with a reference‐less phase contrast navigator. The technique was implemented for nonsubtractive nonenhanced MRA using quiescent‐interval single‐shot MRA. The lower extremity peripheral arteries of eight healthy subjects were imaged using electrocardiographic‐, pulse‐, and self‐gated quiescent‐interval single‐shot. Self‐gated quiescent‐interval single‐shot triggered with 99% accuracy. There were no significant differences in relative contrast, contrast‐to‐noise ratio, or image quality between self‐gated and electrocardiographic‐gated quiescent‐interval single‐shot MRA ( P > 0.05). Image quality with pulse gating was inferior. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.

Erik J Offerman, Christopher Glielmi, Michael Markl, Ioannis Koktzoglou, and Robert R Edelman Radiology, NorthShore University HealthSystem, Evanston, IL, United States, Siemens Healthcare, Chicago, IL, United States, Radiology, Feinberg School of Medicine, Northwestern Univeresity, Chicago, IL, United States, Radiology, Pritzker School of Medicine, University of Chicago, Chicago, IL, United States

Peripheral arterial disease (PAD) is a debilitating disorder. Imaging evaluation is often performed with MRA or CTA, which show anatomic features of a stenosis rather than the hemodynamic abnormalities which produce the symptoms..

To evaluate the signal properties of 2D time of flight (TOF), quiescent‐interval single‐shot (QISS), ECG‐gated 3D fast spin‐echo (FBI), and ungated 3D fast spin‐echo ghost (Ghost) magnetic resonance angiography (MRA) over a range of flow velocities in a pulsatile flow phantom with a 50% diameter stenosis at 1.5T.

Purpose: To completely automate the reconstruction process during noncardiac-gated unenhanced ghost magnetic resonance angiography (MRA).Materials and Methods: Ungated unenhanced ghost MRA of the calf was performed in 16 volunteers. K-means and fuzzy c-means (FCM) clustering algorithms using prominent image features were applied to automatically create angiograms of the calf in volunteers undergoing ungated ghost MRA. Ghost angiograms reconstructed automatically were compared to those created manually on the basis of diagnostic image quality and apparent arterial-to-background contrast-to-noise ratio (CNR). Images were also ranked by an expert user in their order of preference using an ordinal scale.Results: Compared with the ghost angiograms created manually, ghost angiograms reconstructed automatically with the use of clustering analysis provided similar arterial-to-background CNR values. No differences in diagnostic quality or preference were identified between Images reconstructed manually and automaticallly.Conclusion: We present fully automated image reconstruction algorithms for use with ungated and unenhanced ghost MRA. These automated algorithms, based on the use of kappa-means or FCM clustering, can be used to eliminate manual postprocessing that is time-consuming and subject to variability.

Ghost magnetic resonance angiography (MRA) has been proposed as an unenhanced and ungated method for angiography that is based on the presence of ghost artifacts resulting from pulsatile blood flow (1). Although the method is simple to acquire in that cardiac gating is not required, it requires manual post-processing to identify suitable slices in a large stack from which to create an interpretable angiogram. To maximize the contrast of the final angiogram it is necessary to eliminate slices located within the body and to carefully select the slices that contain conspicuous ghost artifacts. This manual post-processing step is time-consuming and can introduce unwanted inter- and intra- observer variability. The purpose of this work was to completely automate the reconstruction process during ungated and non-contrast-enhanced Ghost MRA using image analysis and clustering.

Nanostructures of ferromagnetic oxides having Curie temperatures above room temperature have potential for applications in memory devices and future spin-based electronic applications. In this article, we report on the dc and high frequency magnetic properties of arrays of elliptical CoFe2O4 nanopillars, covering a large area, fabricated by combined electron beam lithography, and a sol-gel based chemical route. The nanopillars were successfully fabricated on insulating oxidized silicon substrates and on epitaxial thin films of ferroelectric BiFeO3. We performed magnetic force microscopy and ferromagnetic resonance spectroscopy on the arrays to probe their magnetic properties. Due to the possible existence of dominant pinning sites, the CoFe2O4 nanopillars are not single-domain even at nanometer size scales.