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2017 Cardiovascular Research Day Abstract Book

35 Identification of

35 Identification of Candidate Long QT Syndrome Type 2 Patients Starting from Exome Sequences Identified in a Biobank Cohort Allison Hall, MS 1 • Don Burgess, PhD 2 • Pierre Fwelo 1 • Jennifer Smith 3 • Corey Anderson, PhD 4 • Craig T. January, MD, PhD 4 • Ann Stepanchick, PhD 4 • Uyenlinh Mirshah, PhD 4 • Jonathan Luo, PhD 4 • Dustin Hartzel, PhD 4 • Michael Murray, MD 5 • Tooraj Mirshahi, PhD 5 • Brian Delisle, PhD 1 1Physiology, University of Kentucky • 2 Physics, Asbury • 3 University of Kentucky • 4 University of Wisconsin • 5 Geisinger Health System Staff Introduction: Every year congenital long QT syndrome (LQTS) is thought to cause sudden cardiac death in hundreds of individuals in the US. Genetic screening potentially could identify LQTS patients before it strikes. However, genetic analyses often find novel rare sequence variants of uncertain physiological significance, and little is known about genetic screening in unaffected populations. Hypothesis: LQTS type 2 (LQT2) is caused by loss-of-function mutations in the rapidly activating delayed rectifier K+ channel gene KCNH2 (Kv11.1). Screening for KCNH2 variants using an approach similar to the Comprehensive In Vitro Proarrhythmia Assay for drug testing will allow the identification of candidate LQT2 patients starting from exome sequences. Methods: Ten KCNH2 mutations from the NCBI ClinVar database listed as “pathogenic”, “suspectedpathogenic”, or “conflicting interpretations” were identified in 10,000 Whole Exome Sequences (WES) from the Geisinger MyCode® cohort. The KCNH2 mutations were screened using Western blot to quantify terminally glycosylated mature Kv11.1 protein (a proxy for Kv11.1 channel trafficking); patch-clamp to measure Kv11.1 channel current (IKv11.1); and computational simulations with a human ventricular action potential (AP) model to predict AP duration (a correlate for the QT interval). Results: Two of the KCNH2 mutations were trafficking-deficient to decrease mature Kv11.1 protein and peak IKv11.1, and five mutations altered normal Kv11.1 channel activation or deactivation. Simulating the decrease in IKv11.1 caused by the trafficking-deficient KCNH2 mutations increased AP duration by >30%, whereas the mutations that disrupted Kv11.1 channel gating did not predict significant changes in AP duration. De-identified Electronic Health Records (EHR) from the Geisinger MyCode® subjects showed that the corrected QT interval (QTc Bazette) for the patients that harbored the trafficking-deficient KCNH2 mutations was ≥480 ms, whereas the average QTc for all EHR database subjects was

36 Optimization of immunomagnetic separation for cryopreserved cord blood and apheresis mononuclear cell fractions derived endothelial progenitor cells Himi Tripathi, PhD 1 • Lakshman Chelvarajan, PhD 1 • Brad J Berron, PhD 2 • Ahmed Abdel Latif, MD, PhD 1 1Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky • 2 Department of Chemical and Materials Engineering, University of Kentucky Staff Introduction: Cardiovascular tissue damage in acute myocardial infarction mainly arises from the loss of blood flow, leading to changes in the composition and function of the ischemic region and heat failure. Multiple studies have examined the utility of CD34+ endothelial progenitor cells (EPCs) for limiting tissue damage and promoting tissue repair after an ischemic event. However, isolation of EPCs using traditional fluorescent activated cell sorting is cumbersome, expensive and time consuming. In this study, we examined the efficacy of novel antigen based methods for EPC isolation from human cord blood. Methods and Results: Immunomagnetic cell sorting protocol to purify CD34+ cells from cryopreserved cord blood and apheresis samples was optimized using MACS ultrapure CD 34 microbead kit. Cell viability, CD 34 purity and endothelial progenitor cells phenotypic expression was assessed using flow cytometer and trypan blue assay. After thawing cryopreserved cord blood, we observed >80 ± 10% viable cells and 95±5% viable apheresis cells. CD34+ purity of 74 ± 16% and 94 ± 1.7% was achieved in cryopreserved cord blood and apheresis samples, respectively. Recovery of CD34+ cells was higher from apheresis (64.6%) in comparison to cord blood (31.3%). Post selection, the expression of EPCs markers was 65.6± 23.2 for CD31 and 90.3 ± 6.6 for CD133 in cord blood and 79.7± 5.5 and 69.6 ± 5.4 in apheresis samples. Additionally, we observed significantly higher recovery and system efficiency when using small input number of CD34+ cells (3.02 ± 2.7 X 106 vs. 31.3% ±54.1 X 106; p

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