title: Phytanic acid accumulation is associated with conduction delay and sudden cardiac death in sterol carrier protein-2/sterol carrier protein-x deficient mice.
abstract: BACKGROUND
  The sterol carrier protein-2 gene encodes two functionally distinct proteins: sterol carrier protein-2 (SCP2, a peroxisomal lipid carrier) and sterol carrier protein-x (SCPx, a peroxisomal thiolase known as peroxisomal thiolase-2), which is involved in peroxisomal metabolism of bile acids and branched-chain fatty acids. We show in this study that mice deficient in SCP2 and SCPx (SCP2null) develop a cardiac phenotype leading to a high sudden cardiac death rate if mice are maintained on diets enriched for phytol (a metabolic precursor of branched-chain fatty acids).
  
  
  RESULTS
  In 210 surface and 305 telemetric ECGs recorded in wild-type (C57BL/6; wt; n = 40) and SCP2 null mice (n = 40), no difference was observed at baseline. However, on diet, cycle lengths were prolonged in SCP2 null mice (262.9 +/- 190 vs 146.3 +/- 43 msec), AV conduction was prolonged (58.3 +/- 17 vs 42.6 +/- 4 ms), and QRS complexes were wider (19.1 +/- 5 vs 14.0 +/- 4 ms). In 11 gene-targeted Langendorff-perfused hearts isolated from SCP2 null mice after dietary challenge, complete AV blocks (n = 5/11) or impaired AV conduction (Wenckebach point 132 +/- 27 vs 92 +/- 10 msec; P < 0.05) could be confirmed. Monophasic action potentials were not different between the two genotypes. Left ventricular function studied by echocardiography was similar in both strains. Phytanic acid but not pristanic acid accumulated in the phospholipid fraction of myocardial membranes isolated from SCP2 null mice.
  
  
  CONCLUSIONS
  Accumulation of phytanic acid in myocardial phospholipid membranes is associated with bradycardia and impaired AV nodal and intraventricular impulse conduction, which could provide an explanation for sudden cardiac death in this model.
authors.affiliation: Department of Cardiology and Angiology, University Hospital Münster, Münster, Germany. moennig@uni-muenster.de
authors.forename: Gerold
authors.initials: G
authors.lastname: Mönnig
authors.forename: Johannes
authors.initials: J
authors.lastname: Wiekowski
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchhof
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Gabriele
authors.initials: G
authors.lastname: Plenz
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Bruns
authors.forename: Lars
authors.initials: L
authors.lastname: Eckardt
authors.forename: Gerd
authors.initials: G
authors.lastname: Assmann
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haverkamp
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Udo
authors.initials: U
authors.lastname: Seedorf
mesh_terms: D000818:Animals; D001919:Bradycardia / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016757:Death, Sudden, Cardiac; D004032:Diet; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006329:Heart Conduction System / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism; D010084:Oxidation-Reduction; D010831:Phytanic Acid / Q000009:adverse effects / Q000378:metabolism*; D013997:Time Factors
chemical_list: D002352:Carrier Proteins; C072087:sterol carrier proteins; D010831:Phytanic Acid