title: Dyscholesterolemia Protects Against Ischemia-Induced Ventricular Arrhythmias.
abstract: BACKGROUND
  Hypercholesterolemia protects against ventricular fibrillation in patients with myocardial infarction. We hypothesize that hypercholesterolemia protects against ischemia-induced reentrant arrhythmias because of altered ion channel function.
  
  
  RESULTS
  ECGs were measured in low-density lipoprotein receptor knockout (LDLr(-/-)), apolipoprotein A1 knockout (ApoA1(-/-)), and wild-type (WT) mice. Action potentials, calcium handling, and ion currents were recorded in ventricular myocytes. Gene expression was determined by quantitative polymerase chain reaction and Western blot. In isolated perfused hearts, regional ischemia was induced and arrhythmia inducibility was tested. Serum low-density lipoprotein (LDL) cholesterol was higher in LDLr(-/-) mice than in WT mice (2.6 versus 0.4 mmol/L), and high-density lipoprotein cholesterol was significantly lower in ApoA1(-/-) mice than in WT mice (0.3 versus 1.8 mmol/L). LDLr(-/-) and ApoA1(-/-) myocytes contained more cholesterol than WT (34.4±2.8 and 36.5±2.4 versus 25.5±0.4 μmol/g protein). The major potassium currents were not different in LDLr(-/-) and ApoA1(-/-) compared with WT mice. The L-type calcium current (I(Ca)), however, was larger in LDLr(-/-) and ApoA1(-/-) than in WT (12.1±0.7 and 12.8±0.8 versus 9.4±1.1 pA/pF). Calcium transient amplitude and fractional sarcoplasmic reticulum calcium release were larger and action potential and QTc duration longer in LDLr(-/-) and ApoA1(-/-) than in WT mice (action potential duration at 90% of repolarization: 102±4 and 106±3 versus 84±3.1 ms; QTc: 50.9±1.3 and 52.8±0.8 versus 43.5±1.2 ms). During ischemia, ventricular tachycardia/ventricular fibrillation inducibility was larger in WT than in LDLr(-/-) and ApoA1(-/-) hearts. Expression of sodium channel and Ca-handling genes were not significantly different between groups.
  
  
  CONCLUSIONS
  Dyscholesterolemia is associated with action potential prolongation because of increased I(Ca) and reduces occurrence of reentrant arrhythmias during ischemia.
authors.affiliation: Departments of Clinical and Experimental Cardiology (A.B., C.A.S., V.W., M.W.V., R.J.v.O., I.E., R.C.), Anatomy Embryology and Physiology (A.O.V.), and Medical Biochemistry (R.O., C.v.R., H.A.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and IHU Institut de Rythmologie et Modélisation Cardiaque, Fondation Bordeaux Université, Bordeaux, France (R.C.). A.Baartscheer@AMC.UVA.NL.
authors.forename: Antonius
authors.initials: A
authors.lastname: Baartscheer
authors.affiliation: Departments of Clinical and Experimental Cardiology (A.B., C.A.S., V.W., M.W.V., R.J.v.O., I.E., R.C.), Anatomy Embryology and Physiology (A.O.V.), and Medical Biochemistry (R.O., C.v.R., H.A.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and IHU Institut de Rythmologie et Modélisation Cardiaque, Fondation Bordeaux Université, Bordeaux, France (R.C.).
authors.forename: Cees A
authors.initials: CA
authors.lastname: Schumacher
authors.affiliation: Departments of Clinical and Experimental Cardiology (A.B., C.A.S., V.W., M.W.V., R.J.v.O., I.E., R.C.), Anatomy Embryology and Physiology (A.O.V.), and Medical Biochemistry (R.O., C.v.R., H.A.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and IHU Institut de Rythmologie et Modélisation Cardiaque, Fondation Bordeaux Université, Bordeaux, France (R.C.).
authors.forename: Vincent
authors.initials: V
authors.lastname: Wekker
authors.affiliation: Departments of Clinical and Experimental Cardiology (A.B., C.A.S., V.W., M.W.V., R.J.v.O., I.E., R.C.), Anatomy Embryology and Physiology (A.O.V.), and Medical Biochemistry (R.O., C.v.R., H.A.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and IHU Institut de Rythmologie et Modélisation Cardiaque, Fondation Bordeaux Université, Bordeaux, France (R.C.).
authors.forename: Arie O
authors.initials: AO
authors.lastname: Verkerk
authors.affiliation: Departments of Clinical and Experimental Cardiology (A.B., C.A.S., V.W., M.W.V., R.J.v.O., I.E., R.C.), Anatomy Embryology and Physiology (A.O.V.), and Medical Biochemistry (R.O., C.v.R., H.A.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and IHU Institut de Rythmologie et Modélisation Cardiaque, Fondation Bordeaux Université, Bordeaux, France (R.C.).
authors.forename: Marieke W
authors.initials: MW
authors.lastname: Veldkamp
authors.affiliation: Departments of Clinical and Experimental Cardiology (A.B., C.A.S., V.W., M.W.V., R.J.v.O., I.E., R.C.), Anatomy Embryology and Physiology (A.O.V.), and Medical Biochemistry (R.O., C.v.R., H.A.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and IHU Institut de Rythmologie et Modélisation Cardiaque, Fondation Bordeaux Université, Bordeaux, France (R.C.).
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: van Oort
authors.affiliation: Departments of Clinical and Experimental Cardiology (A.B., C.A.S., V.W., M.W.V., R.J.v.O., I.E., R.C.), Anatomy Embryology and Physiology (A.O.V.), and Medical Biochemistry (R.O., C.v.R., H.A.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and IHU Institut de Rythmologie et Modélisation Cardiaque, Fondation Bordeaux Université, Bordeaux, France (R.C.).
authors.forename: Ies
authors.initials: I
authors.lastname: Elzenaar
authors.affiliation: Departments of Clinical and Experimental Cardiology (A.B., C.A.S., V.W., M.W.V., R.J.v.O., I.E., R.C.), Anatomy Embryology and Physiology (A.O.V.), and Medical Biochemistry (R.O., C.v.R., H.A.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and IHU Institut de Rythmologie et Modélisation Cardiaque, Fondation Bordeaux Université, Bordeaux, France (R.C.).
authors.forename: Roelof
authors.initials: R
authors.lastname: Ottenhoff
authors.affiliation: Departments of Clinical and Experimental Cardiology (A.B., C.A.S., V.W., M.W.V., R.J.v.O., I.E., R.C.), Anatomy Embryology and Physiology (A.O.V.), and Medical Biochemistry (R.O., C.v.R., H.A.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and IHU Institut de Rythmologie et Modélisation Cardiaque, Fondation Bordeaux Université, Bordeaux, France (R.C.).
authors.forename: Cindy
authors.initials: C
authors.lastname: van Roomen
authors.affiliation: Departments of Clinical and Experimental Cardiology (A.B., C.A.S., V.W., M.W.V., R.J.v.O., I.E., R.C.), Anatomy Embryology and Physiology (A.O.V.), and Medical Biochemistry (R.O., C.v.R., H.A.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and IHU Institut de Rythmologie et Modélisation Cardiaque, Fondation Bordeaux Université, Bordeaux, France (R.C.).
authors.forename: Hans
authors.initials: H
authors.lastname: Aerts
authors.affiliation: Departments of Clinical and Experimental Cardiology (A.B., C.A.S., V.W., M.W.V., R.J.v.O., I.E., R.C.), Anatomy Embryology and Physiology (A.O.V.), and Medical Biochemistry (R.O., C.v.R., H.A.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and IHU Institut de Rythmologie et Modélisation Cardiaque, Fondation Bordeaux Université, Bordeaux, France (R.C.).
authors.forename: Ruben
authors.initials: R
authors.lastname: Coronel
mesh_terms: D000200:Action Potentials; D000818:Animals; D016632:Apolipoprotein A-I / Q000172:deficiency / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D005786:Gene Expression Regulation; D006339:Heart Rate; D006937:Hypercholesterolemia / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000067268:Isolated Heart Preparation; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013107:Sphingolipids / Q000097:blood; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D016632:Apolipoprotein A-I; D020746:Calcium Channels, L-Type; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D011973:Receptors, LDL; D013107:Sphingolipids; D002118:Calcium
keywords: arrhythmia; calcium; cholesterol; ion channel; ischemia