The electrical instability of hypertrophied and failing hearts is caused by delayed repolarisation, which is thought to be due in part to altered levels and/or patterns of expression of ion channel genes. The aim of this study was to investigate changes in the levels and pattern of cystic fibrosis transmembrane conductance regulator (cftr) mRNA expression in a combined pressure and volume overload model of heart failure in the rabbit, using in situ mRNA hybridisation. There was a decrease in cftr mRNA expression, primarily due to a decrease in epicardial expression and, hence, loss of the normal epicardial to endocardial gradient of cftr mRNA expression in the rabbit left ventricle. In contrast there was an increase in atrial natriuretic factor (anf) mRNA expression in the hypertrophied hearts with preferential reexpression in subendocardial regions. The patterns of both cftr and anf mRNA expression in the hypertrophied hearts were similar to those seen in embryonic hearts. This suggests that the reversion to an embryonic pattern of gene expression in cardiac hypertrophy applies to ion channel genes. The loss of the normal transmural gradient of repolarising ion channels is likely to contribute to instability of repolarisation in the hypertrophied heart and hence increased risk of cardiac arrhythmias in patients with heart failure.