MOLECULAR-BASIS OF TRANSIENT OUTWARD POTASSIUM CURRENT DOWN-REGULATION IN HUMAN HEART-FAILURE - A DECREASE IN KV4.3 MESSENGER-RNA CORRELATES WITH A REDUCTION IN CURRENT-DENSITY

Background-Despite advances in medical therapy, congestive heart failu re remains a major cause of death in the developed world, A disproport ionate number of the deaths of patients with heart failure are sudden and presumed to be arrhythmic, Heart failure in humans and in animal m odels is associated with prolongation of the action potential duration (APD), the result of downregulation of K+ currents-prominently, the C a2+-independent transient outward current (I-to). The mechanism for th e reduction of I-to in heart failure is unknown. The K+ channel alpha- subunit Kv4,3, a homolog of the Drosophila Shal family, is most likely to encode all or part of the native cardiac I-to in humans. Methods a nd Results-We used ribonuclease protection assays and whole-cell elect rophysiological recording to study changes in the level of Kv4.3 mRNA and I-to in human tissues and isolated ventricular myocytes, respectiv ely. We found that the level of Kv4,3 mRNA decreased by 30% in failing hearts compared with nonfailing controls. Furthermore, this reduction correlated with the reduction in peak I-to density measured in ventri cular myocytes isolated from adjacent regions of the heart. There was no significant change in the steady-state level of any other mRNA stud ied (HERG, Kv1,4, Kir2.1, Kv beta 1,3, and the alpha 1C subunit of the Ca2+ channel). mRNAs encoding Kv1,2, Kv1,5, and Kv2.1 were found in l ow abundance in human ventricle, Conclusions-These data provide furthe r support for the hypothesis that Kv4.3 encodes all or part of the nat ive cardiac I-to in humans and that part of the downregulation of this current in heart failure may be transcriptionally regulated.