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      Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease

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          Abstract

          The mechanisms underlying chronic kidney disease (CKD)–associated higher risks for life-threatening ventricular tachyarrhythmias remain poorly understood. In rats subjected to unilateral nephrectomy (UNx), we examined cardiac electrophysiological remodeling and relevant mechanisms predisposing to ventricular arrhythmias. Adult male Sprague-Dawley rats underwent UNx (n = 6) or sham (n = 6) operations. Eight weeks later, the UNx group had higher serum blood urea nitrogen and creatinine levels and a longer electrocardiographic QTc interval than did the sham group. Patch-clamp studies revealed epicardial (EPI)-predominant prolongation of the action potential duration (APD) at 50% and 90% repolarization in UNx EPI cardiomyocytes compared to sham EPI cardiomyocytes. A significant reduction of the transient outward potassium current ( I to) in EPI but not in endocardial (ENDO) cardiomyocytes of UNx rats led to a decreased transmural gradient of I to. The reduction of I to currents in UNx EPI cardiomyocytes was secondary to downregulation of KChIP2 but not Kv4.2, Kv4.3, and Kv1.4 protein expression. Incubation of plasma electronegative low-density lipoprotein (LDL) from UNx rats with normal EPI and ENDO cardiomyocytes recapitulated the electrophysiological phenotype of UNx rats. In conclusion, CKD disrupts the physiological transmural gradient of I to via downregulation of KChIP2 proteins in the EPI region, which may promote susceptibility to ventricular tachyarrhythmias. Electronegative LDL may underlie downregulation of KChIP2 in CKD.

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          Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999.

          Knowledge of the excess risk posed by specific cardiovascular syndromes could help in the development of strategies to reduce premature mortality among patients with chronic kidney disease (CKD). The rates of atherosclerotic vascular disease, congestive heart failure, renal replacement therapy, and death were compared in a 5% sample of the United States Medicare population in 1998 and 1999 (n = 1,091,201). Patients were divided into the following groups: 1, no diabetes, no CKD (79.7%); 2, diabetes, no CKD (16.5%); 3, CKD, no diabetes (2.2%); and 4, both CKD and diabetes (1.6%). During the 2 yr of follow-up, the rates (per 100 patient-years) in the four groups were as follows: atherosclerotic vascular disease, 14.1, 25.3, 35.7, and 49.1; congestive heart failure, 8.6, 18.5, 30.7, and 52.3; renal replacement therapy, 0.04, 0.2, 1.6, and 3.4; and death, 5.5, 8.1, 17.7, and 19.9, respectively (P < 0.0001). With use of Cox regression, the corresponding adjusted hazards ratios were as follows: atherosclerotic vascular disease, 1, 1.30, 1.16, and 1.41 (P < 0.0001); congestive heart failure, 1, 1.44, 1.28, and 1.79 (P < 0.0001); renal replacement therapy, 1, 2.52, 23.1, and 38.9 (P < 0.0001); and death, 1, 1.21, 1.38, and 1.56 (P < 0.0001). On a relative basis, patients with CKD were at a much greater risk for the least frequent study outcome, renal replacement therapy. On an absolute basis, however, the high death rates of patients with CKD may reflect accelerated rates of atherosclerotic vascular disease and congestive heart failure.
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            Accelerated atherosclerosis in prolonged maintenance hemodialysis.

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              Modulation of A-type potassium channels by a family of calcium sensors.

              In the brain and heart, rapidly inactivating (A-type) voltage-gated potassium (Kv) currents operate at subthreshold membrane potentials to control the excitability of neurons and cardiac myocytes. Although pore-forming alpha-subunits of the Kv4, or Shal-related, channel family form A-type currents in heterologous cells, these differ significantly from native A-type currents. Here we describe three Kv channel-interacting proteins (KChIPs) that bind to the cytoplasmic amino termini of Kv4 alpha-subunits. We find that expression of KChIP and Kv4 together reconstitutes several features of native A-type currents by modulating the density, inactivation kinetics and rate of recovery from inactivation of Kv4 channels in heterologous cells. All three KChIPs co-localize and co-immunoprecipitate with brain Kv4 alpha-subunits, and are thus integral components of native Kv4 channel complexes. The KChIPs have four EF-hand-like domains and bind calcium ions. As the activity and density of neuronal A-type currents tightly control responses to excitatory synaptic inputs, these KChIPs may regulate A-type currents, and hence neuronal excitability, in response to changes in intracellular calcium.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                17 January 2017
                2017
                : 7
                : 40676
                Affiliations
                [1 ]Department of Medicine, Mackay Medical College , New Taipei, Taiwan
                [2 ]Cardiovascular Research Laboratory, China Medical University Hospital , Taichung, Taiwan
                [3 ]Graduate Institute of Biomedical Sciences, China Medical University , Taichung, Taiwan
                [4 ]Center for Lipid Biosciences, Kaohsiung Medical University Hospital , Kaohsiung, Taiwan
                [5 ]Graduate Institute of Pharmacology, National Taiwan University , Taipei, Taiwan
                [6 ]Vascular and Medicinal Research, Texas Heart Institute , Houston, Texas, USA
                [7 ]Lipid Science and Aging Research Center, Kaohsiung Medical University , Kaohsiung, Taiwan
                [8 ]Center for Lipid Biosciences, Kaohsiung Medical University Hospital , Kaohsiung, Taiwan
                [9 ]Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital , Taichung, Taiwan
                [10 ]Graduate Institute of Clinical Medical Science, China Medical University , Taichung, Taiwan
                Author notes
                Article
                srep40676
                10.1038/srep40676
                5240592
                28094801
                f41920e1-3936-4484-a9c0-a6d1f16f491a
                Copyright © 2017, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 22 August 2016
                : 09 December 2016
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