Phytanic acid accumulation is associated with conduction delay and sudden cardiac death in sterol carrier protein-2/sterol carrier protein-x deficient mice.
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.
Mönnig
Gerold
G
Department of Cardiology and Angiology, University Hospital Münster, Münster, Germany. moennig@uni-muenster.de
Wiekowski
Johannes
J
Kirchhof
Paulus
P
Stypmann
Jörg
J
Plenz
Gabriele
G
Fabritz
Larissa
L
Bruns
Hans-Jürgen
HJ
Eckardt
Lars
L
Assmann
Gerd
G
Haverkamp
Wilhelm
W
Breithardt
Günter
G
Seedorf
Udo
U
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
D002352:Carrier Proteins; C072087:sterol carrier proteins; D010831:Phytanic Acid