15 We measured I to in cells isolated from normal and failing human myocardium and performed ribonuclease protection assays (RPAs) on samples from the same hearts excised from regions immediately adjacent to the sections used for cell isolation. 15 Based on the biophysical properties and pharmacology of expressed Kv4.3 and its abundance in human ventricle, this gene has emerged as the leading candidate for encoding I to in both dogs and humans. For example, significant levels of mRNA encoding the rapidly inactivating K + channels Kv1.4, Kv4.2, and Kv4.3 have been observed in rat ventricle, 14 whereas in canine and human ventricle, there is no detectable Kv4.2, but mRNA encoding Kv1.4, Kv1.5, Kv3.4, and Kv4.3 is present. There are species-specific differences in voltage-dependent K + channel expression. We sought to determine the mechanism of action potential prolongation in human heart failure by quantifying the level of K + channel gene transcripts in normal and failing myocardium. 7 13 The mechanism of the functional downregulation is unknown, but it may involve altered transcription, translation, membrane trafficking, subunit assembly, post-translational modification, degradation of channel proteins, or a combination. Terminal human heart failure is associated with a functional downregulation of the Ca 2+-independent transient outward K + current ( I to) and inward rectifier K + current ( I K1). 10 11 12 Recently, the cellular and molecular bases of action potential prolongation in failing human myocardium were described. Differential expression of a variety of K + currents may be important in defining regional differences in the action potential profile in the heart. Voltage-dependent K + currents mediate repolarization of cardiac myocytes and hence are critical determinants of the action potential duration. 9 However, action potential prolongation itself is arrhythmogenic longer action potentials can be associated with repolarization abnormalities such as afterdepolarizations, which can predispose to triggered arrhythmias. 4 5 6 7 8 Prolongation of the action potential, particularly if it is heterogeneous, can predispose to exaggerated dispersion of repolarization and nonexcitable gap reentry. 3 Action potential prolongation in the absence of other significant electrophysiological changes is a hallmark of failing ventricular myocardium. 1 Ventricular tachyarrhythmias are a common cause of sudden death in patients with heart failure 2 however, the underlying mechanism of these tachyarrhythmias is poorly understood. mRNAs encoding Kv1.2, Kv1.5, and Kv2.1 were found in low abundance in human ventricle.Ĭonclusions-These data provide further support for the hypothesis that Kv4.3 encodes all or part of the native cardiac I to in humans and that part of the downregulation of this current in heart failure may be transcriptionally regulated.Ĭongestive heart failure is a major cause of death worldwide, with as many as 50% of affected patients dying suddenly. There was no significant change in the steady-state level of any other mRNA studied ( HERG, Kv1.4, Kir2.1, Kvβ1.3, and the α1C subunit of the Ca 2+ channel). Furthermore, this reduction correlated with the reduction in peak I to density measured in ventricular myocytes isolated from adjacent regions of the heart. We found that the level of Kv4.3 mRNA decreased by 30% in failing hearts compared with nonfailing controls. Methods and Results-We used ribonuclease protection assays and whole-cell electrophysiological recording to study changes in the level of Kv4.3 mRNA and I to in human tissues and isolated ventricular myocytes, respectively. The K + channel α-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. The mechanism for the reduction of I to in heart failure is unknown. Heart failure in humans and in animal models is associated with prolongation of the action potential duration (APD), the result of downregulation of K + currents-prominently, the Ca 2+-independent transient outward current ( I to). A disproportionate number of the deaths of patients with heart failure are sudden and presumed to be arrhythmic. Customer Service and Ordering Informationīackground-Despite advances in medical therapy, congestive heart failure remains a major cause of death in the developed world.Stroke: Vascular and Interventional Neurology.Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes.Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB).
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