1310 Phytanic Acid Accumulation Is Associated with Conduction Delay and Sudden Cardiac Death in Sterol Carrier Protein-2/Sterol Carrier Protein-x Deficient Mice GEROLD M ¨ ONNIG, M.D., ∗ ,† JOHANNES WIEKOWSKI, PH.D.,† PAULUS KIRCHHOF, M.D., ∗ J ¨ ORG STYPMANN, M.D., ∗ ,† GABRIELE PLENZ, PH.D., ∗ ,† LARISSA FABRITZ, M.D., ∗ ,† HANS-J ¨ URGEN BRUNS, PH.D., ∗ LARS ECKARDT, M.D., ∗ ,† GERD ASSMANN, M.D.,†,‡ WILHELM HAVERKAMP, M.D., ∗ ,† G ¨ UNTER BREITHARDT, M.D., ∗ ,† and UDO SEEDORF, PH.D.† From the ∗ Department of Cardiology and Angiology, University Hospital M¨ unster, M¨ unster, Germany; †Institute for Arteriosclerosis Research at the University of M¨ unster, M¨ unster, Germany; and ‡Institute of Clinical Chemistry and Laboratory Medicine, Central Laboratory, University Hospital M¨ unster, M¨ unster, Germany Phytanic Acid Causes Cardiac Conduction Block. Introduction: 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 (SCP2 null) 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). Methods and 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. Conclusion: 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. (J Cardiovasc Electrophysiol, Vol. 15, pp. 1310-1316, November 2004) branched-chain fatty acids, sudden death, conduction block, bradycardia, sterol carrier protein deficient mouse model Introduction Sudden cardiac death is a frequent and extremely serious often initial manifestation of underlying heart disease. By definition, sudden cardiac death is an unexpected cessation of cardiac function within a short time period. 1 In general, symptoms are evident less than 1 hour before death. At least This study was supported by the Deutsche Forschungsgemeinschaft, Sonder- forschungsbereich 556 A2, Z2 and ZPG4, and in part by the Interdisciplinary Center for Clinical Research, M ¨ unster, Germany. The first two authors contributed equally to this paper. Address for correspondence: Gerold M¨ onnig, M.D., Medizinische Klinik und Poliklinik C–Kardiologie und Angiologie, Universit¨ atsklinikum M¨ unster (UKM), D-48129 M¨ unster, Germany. Fax: 49-251-834-7864; E-mail: moennig@uni-muenster.de Manuscript received 10 December 2003; Accepted for publication 29 June 2004. doi: 10.1046/j.1540-8167.2004.03679.x 50% to 75% of sudden cardiac deaths are caused by ven- tricular fibrillation mostly due to coronary heart disease. 1 Other arrhythmic mechanisms include asystole, bradycardia, electromechanical dissociation, and heart block. 2 The exact pathologic substrates of these bradyarrhythmia-induced sud- den cardiac deaths are currently unknown, but unspecific fi- brosis or hypoplasia of the conduction system has frequently been observed. 3,4 Various fatty acids possess antiarrhythmic or proarrhyth- mic effects as demonstrated in several experimental animal models. 5-8 In the “Paris Prospective Study,” serum nones- terified fatty acids were verified as a risk factor for sudden death in humans, 9 while (n-3) polyunsaturated fatty acids ap- parently prevented ventricular fibrillation. 10 Fatty acid oxida- tion disorders with accumulation of intermediary metabolites often are associated with conduction defects and sudden car- diac death. 11 Sudden death has been described in patients with Refsum disease, a metabolic disorder characterized by accu- mulation of the branched-chain fatty acid (BCFA) phytanic acid due to impaired peroxisomal α-oxidation. 12-15 Patients with Refsum disease present with an increased rate of cardiac