Polyunsaturated fatty acids and acetoacetate downregulate the expression of the ATP-binding cassette transporter A1.

Low HDL cholesterol is a frequent cardiovascular risk factor in diabetes. Because of its pivotal role for the regulation of HDL plasma levels, we investigated in vivo and in vitro regulation of the ATP-binding cassette transporter A1 (ABCA1) by insulin and metabolites accumulating in diabetes. Compared with euglycemic control mice, ABCA1 gene expression was severely decreased in the liver and peritoneal macrophages of diabetic mice. Treatment with insulin restored this deficit. Incubation of cultivated HepG2 hepatocytes and RAW264.7 macrophages with unsaturated fatty acids or acetoacetate, but not with insulin, glucose, saturated fatty acids, or hydroxybutyrate, downregulated ABCA1 mRNA and protein. The suppressive effect of unsaturated fatty acids and acetoacetate became most obvious in cells stimulated with oxysterols or retinoic acid but was independent of the expression of the thereby regulated transcription factors liver-X-receptor alpha (LXRalpha) and retinoid-X-receptor alpha (RXRalpha), respectively. Unsaturated fatty acids and acetoacetate also reduced ABCA1 promotor activity in RAW264.7 macrophages that were transfected with a 968-bp ABCA1 promotor/luciferase gene construct. As the functional consequence, unsaturated fatty acids and acetoacetate inhibited cholesterol efflux from macrophages. Downregulation of ABCA1 by unsaturated fatty acids and acetoacetate may contribute to low HDL cholesterol and increased cardiovascular risk of diabetic patients.

Further evidence of a close anatomical relation between the oesophagus and pulmonary veins.

BACKGROUND: Atrio-oesophageal fistula has been reported as a rare but life-threatening complication of ablation of atrial fibrillation (AF). Therefore, the position of the oesophagus in relation to the left atrium (LA) is of major importance for AF ablation. METHODS AND RESULTS: In order to investigate the possible anatomical variability between the oesophagus and the left atrium, multidetector-row spiral computed tomography (MDCT) of 60 healthy males (age 58.1+/-5.1 years; LA diameter 5.4+/-0.7 x 3.8+/-0.6 cm; LA volume 60.5+/-15.4 ml) was analyzed. The distance between the oesophagus and the ostia of the pulmonary veins (PV) ranged between 0 and 50.7 mm. Especially for the left PV, the oesophagus was closer than 5 mm to the ostia in 29 cases (48%; n = 24 for left superior PV; n = 10 for left inferior PV; n = 0 for right superior PV; n = 1 for right inferior PV). In addition, the oesophagus was very close to the LA wall (0.8+/-0.9 mm; range 0-3.3 mm). Intraobserver variability was 1.1+/-0.7 mm or 3.5%. CONCLUSION: The position of the oesophagus in relation to the LA and the PV demonstrates high variability. In many cases, the oesophagus is very close to the ostia of the PVs and lies only a short distance from the LA wall. Thus, an anatomical localization of the oesophagus may be critical before or during AF ablation to prevent atrio-oesophageal fistula, especially as there is a need for transmural atrial lesions.

Phytanic acid accumulation is associated with conduction delay and sudden cardiac death in sterol carrier protein-2/sterol carrier protein-x deficient mice.

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 (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). 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.